Coordinating effect of ferroptosis and in situ disulfiram toxification for enhanced cancer therapy

Ferroptosis therapy has recently been recognized as a promising strategy for cancer treatment. However, the therapeutic effects of ferroptosis are impaired by insufficient intracellular reactive oxygen species (ROS) production and undesirable drug accumulation. Herein, the metal-phenolic network formed by Cu2+ and tannic acid (TA) as a gatekeeper coating on the surface of disulfiram (DSF)-loaded nanoscale metal–organic frameworks of Fe-TCPP (TCPP = tetrakis (4-carboxyphenyl) porphyrin) (denoted as DSF/Fe-TCPP@Cu-TA) was constructed to achieve apoptosis-ferroptosis collaborative therapy. The pH-depended Cu-TA complex can be broken to accelerate the release of Cu2+, and glutathione (GSH)-initiated DSF/Fe-TCPP degradation promotes the exposure of DSF, Fe3+, and TCPP. The in situ reaction of Cu2+ and DSF can produce bis(diethyldithiocarbamate)-copper (CuET) and is accompanied by hydroxyl radical (·OH) generation for chemotherapy. GSH/TA-mediated Fe3+/Fe2+ conversion can catalyze endogenous hydrogen peroxide (H2O2) to produce ·OH, promoting overwhelming lipid peroxides (LPO) accumulation to sensitize the cancer cells to ferroptosis. When irradiated by a 660 nm laser, TCPP ligand encourages the production of 1O2 for photodynamic therapy (PDT), which can synergize with CuET-based chemotherapy for enhanced apoptosis. The excess generation of ·OH /CuET/1O2 in tumor cells indicates that DSF/Fe-TCPP@Cu-TA can be a satisfactory ferroptosis-apoptosis inducer for efficient cancer therapy.